Chemotherapy dosing of the fluoropyrimidine 5-fluorouracil (5-FU) is currently based on body surface area. However, body surface area-based dosing has been associated with clinically significant pharmacokinetic variability, and as such, dosing based on body surface area may be of limited use. The clinical activity of 5-FU is modest at standard doses, and in general, dosing is limited by the safety profile, with myelosuppression and gastrointestinal toxicity being the most commonly observed side effects. Various strategies have been developed to enhance the clinical activity of 5-FU, such as biochemical modulation, alterations in scheduling of administration, and the use of oral chemotherapy. Studies that have shown an association between plasma concentration with toxicity and clinical efficacy have shown that pharmacokinetically guided dose adjustments can substantially improve the therapeutic index of 5-FU treatment. These studies have shown that only 20%-30% of patients treated with a 5-FU-based regimen have 5-FU levels that are in the appropriate therapeutic range--approximately 40%-60% of patients are underdosed and 10%-20% of patients are overdosed. To date, 5-FU drug testing has not been widely used because of the lack of a simple, fast, and inexpensive method. Recent advances in testing based on liquid chromatography-mass spectroscopy and a nanoparticle antibody-based immunoassay for 5-FU may now allow for routine monitoring of 5-FU in clinical practice. We review the data on pharmacokinetically guided dose adjustment of 5-FU and discuss the potential of this approach to advance therapeutic outcomes.

A139outputs include total costs (Singapore dollars (SGD); 1 SGD=0.82 USD), IFIs avoided, life-years saved, and incremental cost-effectiveness of posaconazole versus fluconazole/ itraconazole. A probabilistic sensitivity analysis (PSA) was conducted, where probabilities of IFI, IFI-related death, and 100-day other cause mortality were assigned beta distributions from trial data. RESULTS: Total costs of prophylaxis with fluconazole/ itraconazole and posaconazole were SGD 4,475 and SGD 4,999, respectively. Corresponding health outcomes were 0.11 and 0.05 IFIs and 2.44 and 2.51 life-years. Incremental cost-effectiveness ratios for posaconazole were SGD 8,150 per IFI avoided and SGD 7,526 per life-year saved. Posaconazole was cost-effective compared to fluconazole/ itraconazole in 94% of PSA simulations at a threshold of SGD 80,000 (commonly cited threshold in Singapore). CONCLUSIONS: Use of posaconazole in place of fluconazole/ itraconazole for prevention of IFIs in a high-risk neutropenic population is costeffective at a willingness-to-pay threshold of SGD 80,000 per life-year saved in Singapore.